Poppelaars Felix, van Werkhoven Maaike B, Kotimaa Juha, Veldhuis Zwanida J, Ausema Albertina, Broeren Stefan G M, Damman Jeffrey, Hempel Julia C, Leuvenink Henri G D, Daha Mohamed R, van Son Willem J, van Kooten Cees, van Os Ronald P, Hillebrands Jan-Luuk, Seelen Marc A
Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
Department of Nephrology, Leiden University Medical Centre, Leiden, The Netherlands.
FASEB J. 2017 Jul;31(7):3193-3204. doi: 10.1096/fj.201601218R. Epub 2017 Apr 10.
The complement system, and specifically C5a, is involved in renal ischemia-reperfusion (IR) injury. The 2 receptors for complement anaphylatoxin C5a (C5aR1 and C5aR2) are expressed on leukocytes as well as on renal epithelium. Extensive evidence shows that C5aR1 inhibition protects kidneys from IR injury; however, the role of C5aR2 in IR injury is less clear as initial studies proposed the hypothesis that C5aR2 functions as a decoy receptor. By Using wild-type, C5aR1, and C5aR2 mice in a model of renal IR injury, we found that a deficiency of either of these receptors protected mice from renal IR injury. Surprisingly, C5aR2 mice were most protected and had lower creatinine levels and reduced acute tubular necrosis. Next, an migration study demonstrated that leukocyte chemotaxis was unaffected in C5aR2 mice, whereas neutrophil activation was reduced by C5aR2 deficiency. To further investigate the contribution of renal cell-expressed C5aR2 leukocyte-expressed C5aR2 to renal IR injury, bone marrow chimeras were created. Our data show that both renal cell-expressed C5aR2 and leukocyte-expressed C5aR2 mediate IR-induced renal dysfunction. These studies reveal the importance of C5aR2 in renal IR injury. They further show that C5aR2 is a functional receptor, rather than a decoy receptor, and may provide a new target for intervention.-Poppelaars, F., van Werkhoven, M. B., Kotimaa, J., Veldhuis, Z. J., Ausema, A., Broeren, S. G. M., Damman, J., Hempel, J. C., Leuvenink, H. G. D., Daha, M. R., van Son, W. J., van Kooten, C., van Os, R. P., Hillebrands, J.-L., Seelen, M. A. Critical role for complement receptor C5aR2 in the pathogenesis of renal ischemia-reperfusion injury.
补体系统，特别是C5a，参与了肾脏缺血再灌注（IR）损伤。补体过敏毒素C5a的两种受体（C5aR1和C5aR2）在白细胞以及肾上皮细胞上表达。大量证据表明，抑制C5aR1可保护肾脏免受IR损伤；然而，C5aR2在IR损伤中的作用尚不清楚，因为最初的研究提出了C5aR2作为诱饵受体的假说。通过在肾脏IR损伤模型中使用野生型、C5aR1和C5aR2小鼠，我们发现这些受体中的任何一种缺乏都能保护小鼠免受肾脏IR损伤。令人惊讶的是，C5aR2小鼠受到的保护最为明显，肌酐水平较低，急性肾小管坏死减少。接下来，一项迁移研究表明，C5aR2小鼠的白细胞趋化性未受影响，而C5aR2缺乏则降低了中性粒细胞的活化。为了进一步研究肾细胞表达的C5aR2和白细胞表达的C5aR2对肾脏IR损伤的作用，构建了骨髓嵌合体。我们的数据表明，肾细胞表达的C5aR2和白细胞表达的C5aR2均介导IR诱导的肾功能障碍。这些研究揭示了C5aR2在肾脏IR损伤中的重要性。它们进一步表明，C5aR2是一种功能性受体，而不是诱饵受体，并可能提供一个新的干预靶点。-波佩拉尔斯，F.，范韦尔霍芬，M.B.，科蒂马，J.，韦尔德胡伊斯，Z.J.，奥塞马，A.，布勒伦，S.G.M.，达曼，J.，亨佩尔，J.C.，勒芬宁克，H.G.D.，达哈，M.R.，范松，W.J.，范库滕，C.，范奥斯，R.P.，希勒布兰德，J.-L.，塞伦，M.A.补体受体C5aR2在肾脏缺血再灌注损伤发病机制中的关键作用。
